Project Summary/Abstract Growing evidence has indicated that exposure of nanoparticles such as MnO2, CuO, TiO2, etc., due to increasing use of these engineered nanomaterials (ENMs), induces nanoneurotoxicity that may pose risks for having neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), etc. However, the mechanisms of in vivo exposure and its potential contribution to neurodegeneration are not well known. Hence, our long-range objective is to study exposure of ENMs such as metal oxide nanoparticles and their nanoneurotoxicity and potential correlation to human diseases such as AD using both in vitro and in vivo disease models and imaging modalities. The specific hypothesis for this proposal is that exposure of CuO nanoparticles increases blood-brain barrier (BBB) permeability, enhances neurodegeneration, exacerbates cerebral A? amyloid pathology and associated neuroinflammation and redox stress, alter brain cytokine, biometal, and energy metabolic profiles. We base the hypothesis on previous observations and current key pilot data which suggest that: (i) long-term exposure to severe air pollution (highly possible exposure of metal oxide nanoparticles) is associated with neuroinflammation, BBB disruption, and A?1-42 accumulation (the salient neuropathological features of AD); (ii) CuO nanoparticle exposure increases BBB permeability via inhalation; (iii) exposure of CuO nanoparticles induce in vitro neurotoxicity, inflammation, and oxidative stress. To test our current hypothesis, we will (i) determine the effects of CuO nanoparticle inhalation on in vivo blood- brain barrier integrity and enhanced neurodegeneration; (ii) assess the effects of CuO nanoparticle inhalation on neuroinflammation, cerebral oxidative stress and A? amyloid pathology; (iii) evaluate the effects of CuO nanoparticle inhalation on memory function, biometal profiles in A? amyloid plaques and brain metabolic activities. We will use in vivo microSPECT (micro Single Photon Emission Computed Tomography) imaging and histology detection methods, cytokine microfluidic biochip assays, oxidative stress (4-HNE) and A? ELISA assays, high-energy X-ray fluorescence microscopy (-XRM) via the measurement of x-ray absorption spectra (-XAS) and x-ray absorption near edge spectra (-XANES) coupled with laser capture microdissection (LCM) tissue procuring technique, MRI/MRS, Morris Water Maze (MWM) memory test, and PS1/APP AD transgenic mouse model to achieve these experimental aims. Using our integrated experimental approaches, we believe that we will gain knowledge that can contribute to the making of public policy on regulating nanoparticle exposure and its neurotoxic effects upon the Central Nervous System (CNS), and further our understanding about potential risk of metal oxide nanoparticle exposure for neurodegeneration. More importantly, it will establish an experimental paradigm that will be very useful for investigating the nanoneurotoxicity and its potential contribution to etiopathogenesis of neurodegenerative diseases such as AD.